X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant

Pegoraro, Elena; Carelli, Valerio; Zeviani, Massimo; Cortelli, Pietro; Montagna, Pasquale; Barboni, Piero; Angelini, C.; Hoffman, Eric P.

doi:10.1002/(sici)1096-8628(19960202)61:4<356::aid-ajmg10>3.0.co;2-r

Cited by 36 publications

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References 25 publications

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“…However, the penetrance is incomplete and it is still not clear why only 50% of males and 10% of females develop visual loss 30. Attempts to identify a relevant locus on the X chromosome have not been successful,31 and the difference may be the result of gender related anatomical and physiological differences 32…”

Section: Mtdna Mutations Do Not Exert Their Effects In Isolationmentioning

confidence: 99%

Mitochondrial DNA analysis: polymorphisms and pathogenicity

et al. 1999

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The investigation of mtDNA disease can be relatively straightforward if a person has a recognisable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulties arise when no known mtDNA defect can be found, or when the clinical abnormalities are complex and not easily matched to those of the more common mitochondrial disorders. We will describe here the difficulties that can be encountered during the identification of pathogenic mtDNA mutations and the approaches that can be used to confirm, or eliminate, a likely pathogenic role, in either single gene diseases or in multifactorial disorders.

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Section: Mtdna Mutations Do Not Exert Their Effects In Isolationmentioning

confidence: 99%

Mitochondrial DNA analysis: polymorphisms and pathogenicity

et al. 1999

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Leber hereditary optic neuropathy: Potential opportunities/potential pitfalls for drug therapy of optic nerve degenerative disorders

Howell

1999

Drug Dev. Res.

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Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiologic event is a mutation in the mitochondrial genome. The primary mitochondrial mutation is necessary—but not sufficient—for manifestation of the optic neuropathy, and secondary genetic and/or epigenetic risk factors are also involved. There is broad agreement that mutations at mtDNA nucleotides 3460, 11778, and 14484 are primary LHON mutations and that they account for 95% of the classic LHON cases in Caucasians of northern European descent. It appears that these three primary LHON mutations are associated with respiratory‐chain dysfunction, but the derangement may be relatively subtle and/or vary among different tissues. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The specific pattern of neurodegeneration in LHON may arise from a mitochondrial “chokepoint” in the region of the optic nerve that spans the nerve head and lamina cribosa. It is hypothesized that in the acute phase, a respiratory‐chain dysfunction “crisis” leads to axoplasmic stasis and swelling, initially in the chokepoint, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a subset of ganglion cells and a substantial recovery of vision occurs. However, in other patients, a cell death pathway (probably apoptotic) is activated, with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve with an irreversible loss of vision. The complex etiology of LHON may allow therapeutic intervention at any one of several steps, but there are also potential pitfalls. Drug Dev. Res. 46:34–43, 1999. © 1999 Wiley‐Liss, Inc.

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X‐inactivation pattern in multiple tissues from two leber's hereditary optic neuropathy (LHON) patients

Pegoraro

Vettori

Valentino

et al. 2003

American J of Med Genetics Pt A

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The more frequent manifestation of ophthalmological abnormalities in males, relative to females, is an unexplained feature of Leber's hereditary optic neuropathy (LHON) that suggests an X-linked modifying gene acting in concert with the pathogenic LHON mitochondrial DNA (mtDNA) mutation. In addition, segregation analysis of the optic neuropathy in LHON pedigrees was compatible with the presence of a recessive-modifying gene on chromosome X. According to this two-locus model, females would be affected only if homozygous or if they were susceptible to skewed X-inactivation. Attempts both to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X-inactivation in affected females were unsuccessful, although the inactivation pattern was only studied in DNA isolated from blood cells. We had the opportunity to analyze a wide range of tissues at autopsy, including the optic nerves and the retina, from two LHON female patients. We found no evidence of skewed X-inactivation in the affected tissues, thus weakening further the hypothesized involvement of a specific X chromosome locus in the pathophysiological expression of LHON.

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X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant

Cited by 36 publications

References 25 publications

Mitochondrial DNA analysis: polymorphisms and pathogenicity

Mitochondrial DNA analysis: polymorphisms and pathogenicity

Leber hereditary optic neuropathy: Potential opportunities/potential pitfalls for drug therapy of optic nerve degenerative disorders

X‐inactivation pattern in multiple tissues from two leber's hereditary optic neuropathy (LHON) patients

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